iThis proposal is submitted in response to PAR-03-056 and is applicable to research objective number 18, Functional Senescence. Senescence is reflected in the deterioration of a number of physiological systems with age. Age-related decline in the immune system, or immunosenescence, is a particularly serious consequence of aging. In addition to greatly increasing the risk of infection in the elderly, age-specific immune dysfunction may also reduce life span. Studies of humans and other vertebrates have identified many age-related changes in the cellular components and physiology of the immune system that contribute to reduced immune function. However, the underlying causes of these changes, including the genetic influences on immunosenescence, are poorly understood. A promising and novel approach to this general problem is to apply recent advances in statistical and quantitative genetics to map the location of genes that influence immunosenescence. This project will use Drosophila melanogaster as a model system to accomplish two goals: 1) to document the extent of genetic influences on natural variation in the age-specific immune response, and 2) to map the position of genetic regions that influence this trait. One hundred lines of flies recently derived from a natural population will be screened for their ability to clear infection from septic injury at young and old age. From this screen, two mapping populations will be constructed to identify the chromosomal positions (quantitative trait loci or QTL) that influence the age-specific ability to clear infection from septic injury. These data will lay the groundwork for future studies to identify the specific genes that contribute to immunosenescenee. In the long term, understanding the genetic basis of tmmunosenescence may prove useful for the treatment of age-related immune dysfunction in humans, and provide genetic markers to identify those at risk for accelerated immunosenescence.